Spirocyclohexanes and methods of preparation thereof



Emile Eatented Jan. 5, 1954 SPIROCYCLOHEXANES AND METHODS OF PREPARATION THEREOF Gilbert Forrest Woods, Jr., and Louis H. Schwartzman, Silver Spring, Md.

No Drawing. Application November 24, 1951, Serial No. 258,091

6 Claims. (Cl. 260-465) This invention relates to compounds of the spirocyclohexane type and methods of preparation thereof.

More particularly, the invention relates to the synthesis of compounds of the spirocyclohexane type, particularly those having analgesic properties such as possessed by morphine and other opiates derived from natural sources.

Considerable effort has been directed in the past toward the synthesis of suitable analgesics as substitutes for morphine and the like, particularly in view of the fact that the principal source of supply of morphine and related compounds is dependent upon natural sources, most of which are presently located in the Orient. In an effort to produce chemically synthesized analgesics domestically on an economically practicable basis, and to provide a source of analgesics independent of natural supplies of raw materials, many attempts have been made to synthesize various analgesics as substitutes for morphine and the like, some of the more recently developed compounds being OOOEt (.L} H: Demerol pensive to manufacture from readily available raw materials but, in addition, have satisfactory analgesic properties and are of sufiiciently low toxicity to permit safe use by human beings.

In its more specific aspects the present invention pertains to the synthesis of analgesic compositions Of the spirocyclohexane type by employing cyclohexanone as a starting material and producing therefrom a large number of new, novel and useful analgesic compounds contain ing a quaternary carbon atom in the molecule and, in addition, either a primary, secondary, or tertiary amine group.

The invention also provides new and novel methods of preparing the compounds described herein, such methods being particularly advantageous in view of the simplicity of the procedures, economic practicability and comparatively high yields of the intermediates and the end products without the use of complicated or expensive starting materials, apparatus, or processes.

The intermediates required for synthesis of the compounds of the present invention may be prepared, for example, in the manner described in copending application Serial No. 150,806, filed March 20, 1950, now Patent No. 2,586,486 by using cyclohexanone as a starting material, treating it with a mixture of calcium carbide and potassium hydroxide to yield an acetylenic glycol such as 1,1'-ethynylene-bis-cyclohexanol according to the reaction:

0 H OH on 020 Ca0 KOH This glycol (II) is then dehydrated to the dieneyne (III) by, for instance, heating the above glycol under reflux conditions with dilute sulfuric acid as follows:

' The compound thus obtained is then cyclized and hydrated, for example, by refluxing with formic acid, thus producing as intermediates, cyclic ketones such as spiro[cyclohexane-Ll-A '-tetrahydroindanone-B'] (IV) and its isomer spiro- 3 [cyclohexane 1,1'-A tetrahydroindanone-Zi] (V) in accordance with the following reaction:

OEC

(III) (IV) To produce the analgesic compounds of the present invention, the cyclic ketones (IV) and/or (V) are converted to the ketone (VI) and subsequently to its oxime (VII) according to the reaction:

' 'l l i I g Catalyst I u N \I 0 V (VI (VII and thereafter the oxime (VII) is hydrogenated in the presence of a catalyst to produce an analgesic spiroindane in accordance with the reaction:

and/or By further treatment of the spiroindane (VIII) according to the following reaction, compound (IX) is obtained, this compound being an important intermediate for the preparation of the compounds of the present invention:

HCOOH, orno 8 o c /CH: 11/ NH, E N

(VIII) (IX) The compounds (VIII) and (IX) and methods of preparation thereof are disclosed and claimed in copending application Serial No. 150,808, filed March 30, 1950 now Patent No. 2,585,969.

The compounds of the present invention, as distinguished from those disclosed and claimed in said copending applications Serial Nos. 150,808 now Patent No. 2,585,969 and 150,810 now abandoned, each filed March 20, 1950, in that the present compounds are substituted spirocyclohexanes of the type:

wherein R1 and R2 are selected from the group consisting of hydrogen and lower alkyl groups and X is selected from the group consisting of halogens, amino groups, hydroxyl, nitro, alkoxy groups, nitrile, N-substituted aminomethyl groups, O-acyl groups, acyl groups, alkyl carbinol groups, and alkyl carbinol ester groups.

A series of compounds of the substituted spirocyclohexane type coming within the scope of the present invention may be prepared, for example, by the following illustrative reactions:

NEC

It is an object of the present invention, therefore to provide a series of substituted spiroindanes. More particularly it is an object to provide substituted spiroindanes having analgesic properties. It is a further object of the present invention to provide a series of substituted spiroindanes having a quaternary carbon atom and, in addition, a primary, secondary or tertiary amine group in the molecule. It is a still further object of the present invention to provide methods of preparation of the compounds of the invention.

For purposes of illustration, but without intending to limit the scope of the patent thereto, representative methods and compounds of the present invention are described in the following examples:

Example I A compound of the type:

wherein X is the nitro group and R1 and R2 are methyl groups is illustrated as follows:

A mixture of 5 grams of the amine, spiroEcyclohexane 1,1 3-dimethylaminoindanel, prepared in accordance with application Serial No. 150,808, referred to herein above, in 100 ml. carbon tetrachloride is cooled to 0 C. and with vigorous stirring, 9.4 ml. of concentrated sulfuric acid is added dropwise. The mixture is cooled to 3 C., and a solution of 2.75 grams of potassium nitrate in 8.4 m1. of concentrated sulfuric acid is added dropwise with vigorous stirring over a period of minutes. The temperature at the end of the addition was 0 C., the resulting two phase system is stirred at this temperature for an hour and the carbon tetrachloride layer decanted away. Upon pouring the brown oil with stiror Halogen ring onto ice, a precipitate is formed which is difficult to filter. Therefore, it is neutralized with ammonium hydroxide and extracted with ether. This extract is dried and filtered. Absolute alcohol (10 ml.) saturated with hydrogen chloride gas is added to the filtered dry ether extract to give 7 grams of spiro[cyclohexane-1,1'- 3' dimethylamino x nitroindanelhydrochloride. This is clarified and crystallized from alcohol-ether to give 4 grams of material melting at 258-260.

The free amine, spiro[cyclohexane-1,1'-3'-dimethylamino-x-nitroindane] boils at 182-185 C. at 1.8 mm. This compound has the formula:

OzN-

7 V I Example 1(a) A compound having the formula:

may be prepared as follows:

SpiTMCycZOhexane-LZ' 3 amino a: nitroindane].-This compound was prepared in a manner similar to that for spirolcyclohexane- 1,1'-3'-dimethylamino x nitroindane] in 59 yield by nitrating the primary amine, spiroEcyclohexane 1,1 3 aminoindane]. The nitroamine after recrystallization from methanol-Water mixtures and sublimation at reduced pressure melted at 97-99 C. The amine hydrochloride formed in the usual manner and recrystallized from alcohol-ether mixtures melted at 268-273 (decomp) Example II An extremely effective analgesic compound of the type:

wherein X is the amino group and R1 and R2 are lower alkyl groups may be prepared as follows:

A mixture of 3.7 grams of spiro[cyclohexane 1,1'-3'-dimethylamino x nitroindane] hydrochloride dissolved in 50 ml. of 95% alcohol is stirred and refluxed. To this refluxing mixture, 17.7 grams of SnC12-2H2O dissolved in 16.9 ml. concentrated hydrochloric acid and 21 ml. 95% alcohol is added over a period of twenty minutes. After boiling for an additional thirty minutes, the alcohol is removed under reduced pressure and the resulting complex is decomposed with a large excess of aqueous potassium hydroxide. The solution is then extracted with ether, the ether is dried over magnesium sulfate and upon distillation of the dried ether extract under reduced pressure 2.9 grams of solid di-amine is obtained as a residue. The di-amine, spirolcyclohexane-1,1 x amino 3 dimethylaminoindane], is sublimed at 120 C. and 1 mm. This affords a white crystalline sample melting at 114- 116 C. The compound has the formula:

This compound possesses the analgesic efiects on white mice described in the following chart:

M. E. D. L. Dan

5 rug/kg. body weight 75 mg-I g. body weight Example II (a) A compound having the formula:

8.. Example III A compound having the formula:

NEG-

o H N-OHz may be prepared as follows:

SrflroEcyclohemane 1,1 a: cyano 3 d methylaminoz'ndanel.-A solution of 10 g. (.041 mole) of the diazonium salt of spiroEcyclohexane 1,1 x amino 3' dimethylaminoindane] cooled to 0 was carefully neutralized with sodium bicarbonate. This solution was added dropwise to a freshly prepared mixture of 0.041 mole of cuprous cyanide covered with 200 ml. of toluene which was cooled to 0 and vigorously stirred. After the addition the mixture was stirred for onehalf hour at 0, four hours at room temperature, and finally heated to 50 for three hours. The cooled mixture was made alkaline with sodium hydroxide and extracted with ether. The organic layer was extracted with dilute hydrochloric acid. The aqueous layer was neutralized, extracted with ether, dried, and the dried ether layer was concentrated under reduced pressure to yield 8 g. of a dark brown oil. The hydrochloride, made by passing hydrogen chloride gas into an ether solution of the amine, was dissolved in alcohol and treated with a few grams of stannous chloride and hydrochloric acid and finally charcoal to effect an efiicient decolorization. The slightly yellowish hydrochloride was recrystallized from alcohol and melted at 257-260.

The free cyanoamine, spiro[cyc1ohexane-1,1- x-cyano-3-dimethylaminoindane], was regenerated with dilute ammonium hydroxide and after recrystallization from petroleum-ether (20-40) and sublimation at reduced pressure melted at 81- 82.

Example IV A compound of the type:

wherein X is the hydroxyl group and R1 and R2 are methyl groups may be prepared as follows:

3.5 grams of spiro[cyclohexane-1,1'-x-amino- 3-dimethylaminoindane] prepared in accordance with the procedure of Example II, is dissolved in a solution of 2.2 ml. concentrated sulfuric acid in 75 ml. water, is cooled to 0 C., with an icesalt bath and is stirred vigorously. Then 1.1 grams of sodium nitrite in 10 ml. of water cooled to 0 C. is added dropwise over a period of ten minutes. After destroying the excess nitrous acid with urea, 5 m1. of concentrated sulfuric acid in 5 ml. of water is added and the mixture is heated on the steam bath to 97 C. for one hour. Clarification of the red aqueous solution with charcoal and subsequent cooling yields 1.75 grams of the white crystalline phenolic amine sulfate. The crystals are recrystallized twice from about 400 ape-5,296

ml. of boiling water, to give colorless material which melts at 250-255 C. .Anal-ysis showed this compound to be the dihydrate of the amine sulfate. Upon addition of ammonium hydroxide to thi material and subsequent crystallization from alcohol-water mixtures spiro[cyclohexanel,1- 3'-dimethylamino-x-hydroxy-indane] is obtained which melts at 170-172 C.

This compound has the formula:

Example V A compound of the type:

wherein X is the hydroxyl group and R1 and R2 are hydrogen maybe prepared as follows:

A solution of sprio[cyclohexane-1,1'indanone- 3'] (18.2 g.) dissolved in '100 'ml. of concentrated sulfuric acid is cooled to C. To this is added dropwise g. of potassium nitrate dissolved in 30 ml. of concentrated sulfuric acid with stirring over a period of 1 A; hours, after which the stirring was continued for an additional hour at 0 C. The reaction mixture is then poured with vigorous stirring onto ice. The yellow solid precipitate of nitroketone is filtered and the solid fractionally crystallized from acetone and 18 g. of material melting at 193-195 is obtained. Further crystallization from benzene yields hexagonal, slightly yellow crystals of spiro cyclohexane-Ll-x-nitroindanone-3l melting at 195-1955".

A solution of spiro[cyclohexane-1,1'-x-nitroindanone-3] (14.1 g.) in 90 ml. of 95% alcohol is stirred-and refluxed; .to this isadded indropwise manner a solution of 41 g. ShClaZI-IQO in 40 ml. of concentrated hydrochloric acid and 20ml. of 95% alcohol. After refluxing for an additional thirty minutes, the solvent is removed under reduced pressure and the complex decomposed with a large excess of concentrated potassium hydroxide solution. The alkaline solution is extracted with ether, the ether extract dried and the dry extract is distilled under reduced pressure to leave as a residue, spirolcyclohexane-1,1-x-aminoindanone-3'l. After crys tallization of theresiduefrom benzene-petroleum ether mixtures and subsequent sublimation at 120 C. at 0.5 mm., 11 g. of the aminoketone is obtained which melts at 125-126 C.

Spiro cyclohexane- 1 ,"1 -rx -aminoindanone 3 "1 (10.5 g.) in a solution of 11 mlhof concentrated sulfuric acid and 80 ml. of waterisdiazotizedat 3-5 G. with 3.5 g. Na'Noz inZO-ml. of water over a period of thirty minutes. After decomposition of the excess nitrous acid with urea, the solution is filtered and, after addition of 5 ml. ofconcentrated sulfuric acidin ZO mlof water is heated for 1% hours on a steam ".cone. After cessation of 10 the nitrogen evolution, the phenolic ketone appears as an orange oil, which solidifies on cooling. The solid phenolic ketone is dissolved in ether and extracted with-aqueous potassium hydroxide, and the alkaline extract neutralized carefully with hydrochloric acid. The resulting yellow precipitate is recrystallized from alcohol-water and then sublimed at 160 C. and0.03 mm. to yield 7.6 g. of spiro cyclohexane-1,l -x-hydroxyindanone 3 'l which melts at 159-160 C.

Spiro [cyclohexane- 1,1 x-hydroxyindanone.. 3'] (5 g.) is added to a mixture of hydroxylamine hydrochloride (5 g.), pyridine (14 m1.), and anhydrous alcohol (30 ml.), and the solution is refiuxed for 2 hours. Removal of the solvent under reduced pressure, and recrystallization of the crystalline mass from alcohol-water mixtures affords the oxime of spiro [cyclohexane-1,1'-x-hy- =droxyindanone-3] (5 g.) which melts at 182- The oxime of spiro[cyclohexane-1,1-x-hy droxyindanone-3'] (13 g.) is hydrogenated at room temperature and 20 pounds of hydrogen with 0.5 g. of platinum oxide as a catalyst in ml. of glacial "acetic acid. After cessation of hydrogen absorption, the catalyst is removed by filtration. The filtrate is cooled and neutralized with ammonium hydroxide to talline precipitate. After crystallization from 50% alcohol-water mixtures, 10 g. of spiro [cyclohexane- 1,1-3-amino-x-hydroxyindane] is obtained which melts at 227-228 C.

This compound'has the formula:

OBI-- H/ N-H Example V(a) The compound of Example V may be prepared by an alternative method, as follows:

SpiroEcYclohexane 1,1'-3-aminoindanel can be nitrated as the 'N-a'cetyl derivative in a solution of carbon tetrachloride with either fuming nitric acid or a mixture of potassium nitrate and sulfuric acid. The resulting 'nitro-N-acetylamine can be isolated in the usual manner and subse- Example VI The compound of Example IV may be obtained by another method, as follows:

A mixture of spiro[cyclohexane-1,1'-3'-aminox-hydroxyin-danel (0.5 :g.) and 0.5 g. of 87% formic acid is cooled and to the cooled solution, 0.4:g.of'37% formaldehyde is added. Warming on asteam "cone caused an evolution of carbon "dioxide; heating .is :continued for twelve hours.

The solution is concentrated under reduced pressureand 'then neutralized with ammonium hydroxide to -yie'ldayellow precipitate. Crystallization of the :compound from acetone affords a yield a white crys- 11 white crystalline compound which melts at 169- 170 and gives no depression in a mixed melting point determination with spiro[cyclohexane- 1,1 3 dimethylamino-x-hydroxyindane] prepared as indicated earlier.

Example VII A compound of the type:

wherein X is a halogen and R1 and R2 are methyl groups may be prepared as follows:

Spiro[cyclohexane 1,1 x amino 3' dimethylaminoindanel can be diazotized as indicated in Example III. The diazonium salt solution is then treated with potassium iodide and the mixture stirred at room temperature until the evolution of nitrogen ceases. Isolation in the usual manner affords spiro[cyclohexane1,1-3

. dimethylamino-x-iodoindane].

Example VIII A compound of the type:

K H N-Ri Example IX A compound of the type:

wherein X is acetate and R1 and R2 are methyl groups may be prepared as follows: SpiroEcyclohexane 1,1 3' dimethylaminox-hydroxyindane] is dissolved in 4 molar equivalents of acetic anhydride and then a catalytic amount of pyridine added. After several days at room temperature, the solvent is removed under reduced pressure to yield spiro[cyclohexane-1,1- x-acetoxy-3 -dimethylaminoindane] Example X A compound having the formula:

may be prepared as follows:

Spiroicyclohexane 1,1 3' dimethylaminox -(1 hydroxyethyl)indane].To an efiiciently stirred solution of 20 m1. of 1.3 molar lithium aluminum hydride in ether was added dropwise 3 g. of spiro(cyclohexane-1,1'-x-acetyl-3'dimethylaminoindane) in ml. of anhydrous ether. After the addition, the mixture was stirred for an additiona1 half hour and then sufficient water was added in the cold to just decompose the excess reagent and the complex. The ether layer was washed with water, dried over anhydrous magnesium sulfate, and after removal of the drying agent, concentrated to give 3 g. of the hydroxy compound. Since the substance was difficult to handle, the hydrochloride was prepared by passing dry hydrogen chloride gas through an ether solution of the amine and after recrystallization from alcohol-ether mixtures melted at 245-247.

Example X (a) A compound having the formula:

may be prepared as follows:

Spiro [cyclohexane1,1-3-dimethyZamino-x- (l-hydroxy-batyl)indancl.-In the same manner as above 3.4 g. of spiro (cyc1ohexane-1,l-x- (n-butyryl)-3-dimethylaminoindane) was reduced with lithium aluminum hydride to yield 3.4 g. of the hydroXy compound which was then converted to the hydrochloride, M. P. 210-211", after recrystallization from alcohol-ether mixtures.

Example XI A compound having the formula:

may be prepared as follows:

Spiro [cyclohexane 1,1-3'-dimethylamino-x- (l-hydroxybutyl) indane] (0.9 g.) was mixed with 5 ml. of acetic anhydride and 1 ml. of pyridine. The mixture was heated slightly on a steam cone to affect solution and then allowed to stand at room temperature for three days. The solvent was then removed under reduced pressure to yield as a very viscous oil, the acetyl A compound having the formula:

Z A H were CH3 (IIHQ may be'prepared as'fo'llows:

Spiro [cyclohexane-1,1 3"-dimethy1 amino-x- (l-hydroxyethyDindane] (1.1 g.) in 20 ml. of anhydrous ether was added dropwise to the Grignard reagent prepared from 1.27 g. of ethyl iodide and 0.2 g. of magnesium. After stirring the reaction at room temperature for an additional hour, 1.1 m1. of acetic anhydride in 20 ml. of anhydrous ether Wasadded dropwise-and the mixture stirred for 22 hours. The mixture was decomposed on ice and ammonia and the ether layer was washed and dried with anhydrous magnesium sulfate.

The dried ether solution was concentrated to yield 0.5 g. of the oily ester.

In the same manner the propionyl ester was formed using propionic anhydride in place of aceticanhydride.

Example XIIII A compound having theformula:

may be prepared as follows:

Spiro [cyc'Zohexane-I ,1 -3'-dimethylamino-.xethoryidcmcl-To a cooled solution of 5 ml. of 90% formic acid and 6 m1. of 40% formaldehyde Was added 2.1 g. of spiro(cyclohexane-1,1-3- amino-x-ethoxyindane) hydrochloride and then the mixture was slowly warmed on a steam bath until the evolution of carbon dioxide'had ceased. The mixture was then concentrated under reduced pressure, made alkaline, and extracted with ether. The ether layer was extracted with dilute hydrochloric acid, which 'in turn was neutralized, extracted with ether and the ether extract dried over anhydrous magnesium sulfate. After removal of the drying agent, dry hydrogen chloride gas was passed into the solution give 2 g. of crystalline amine hydrochloride, which after recrystallization from acetone melted at 211-213.

Example XIV A compound having the formula:

may beprepared asfollows:

Spiro .[cyclohewane 1.,1' a: propionyZ-3'-dimethylaminoindaneL-In the same manner as above, 7 g. of theamine, 14 g. of anhydrous aluminum chloride, and 4.3 g. of propionic anhydride was allowed to react in carbon disulfide to produce 1.5 g. of spiro [cyclohexane-1,1-xpropionyl 3' dimethylaminoindanel B. P. 155/0.5 mm., M. P. 56-58 from petroleum ether (20-40).

The hydrochloride made in the usual manner was recrystallized from alcohol ether mixtures and melted at 252-255.

Example XV A compound-having the formula:

may be prepared as follows:

'Spiro [cyolohesccme 1,1 :c(nbutyryZ)-3'-dimethyZaminoindane].-In the same manner as above, 7 g. of the amine, 11 g. of anhydrous aluminum chloride, and 3.5g. of n-butyryl chloride was allowed to react in carbon disulfide to produce 4.4 g. of spiro [cyc10heXane-1,1-x(nbutyryl) 3 dimethylaminoindane]; B. P.

150/0.4'mm., M. P. 48-49 from petroleum-ether (20-40").

The hydrochloride made in th usual manner was recrystallized from alcohol-ether mixtures and melted at 215-218 C.

Example XVI Acompoundhaving theformula:

and ml. of carbon disuifide. A vigorous reaction ensued, which caused hydrogen chloride to be evolved, and which caused the carbon disulfide to reflux. After the initial reaction had subsided, the mixture was refluxed for an additional eighteen hours. The cooled mixture was 'th'enpoured with stirring into an ice-sodium hydroxide solution and the organic layer extracted with ether. The ether layer was extracte with dilute hydrochloric acid, the aqueous layer made alkaline, extracted with ether, and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, distillation yielded 15 :g. of unreacted amine (B. P. 96-106/.08-.09) and 5 .7 'g. 'o'fspiro [cyclohexane-1,1-X-acetyl-3'- dimethylaminoindane] which boiled at -160 at 1 mm. The ketoamine was crystallized from petroleum ether (20-40% in a Dry Ice bath and after two sublimations melted at 90-92".

The hydrochloride made in the usual manner was recrystallized from methanol-ether mixtures and melted at 25 1-255 (decomp.)

Example XVII A compound having the formula:

C2HaO- H/ \NH2 may be prepared as follows:

Spiro [cyclohextme-Ll-a:-niirindan0ne3] Ten grams of potassium nitrate in 30 ml. of concentrated sulfuric acid was added dropwise with stirring to a solution of 1 3.2 g. of spiro [cyclohexane-1,1-indanone-3l, in 100 ml. of concentrated sulfuric acid cooled to 0 by means of an ice-salt bath. This addition took one and a quarter hours and at no time was the temperature greater than 5. The mixture was stirred an additional hour at 0 and poured with stirring onto cracked ice. The yellow solid was washed with water, dissolved in 500 ml. of hot acetone, clarified and allowed to crystallize slowly overnight. In this manner, 13.7 g. of yellow hexagonal crystals melting at 193-194= were obtained, concentration of the mother liquors and finally addition of water produced further fractions which melted at 193-19 1 and gave no mixed melting point depression with the first fraction. Each fraction was then recrystallized from acetone, benzene, and then acetone, but in each case the melting point was 195-195.5 and gave no mixed melting point depression with other fractions. It seems probable therefore that nitration of the ketone under these conditions led to a single positional isomer. The total yield of spiro [cyclohexane- 1,1-x-nitroindanone-3l was 18 g. or 83%,

Spiro [cyclohexane 1,1 .r-aminoindanone- 3'].-To a refluxing solution of 1 1.1 g. of the nitroketone in 90 m1. of 95% alcohol was added dropwise, with stirring, 41 g. of stannous chloride dihydrate in .0 ml. of concentrated hydrochloric acid and 20 ml. of 95% alcohol. After the addition, the yellow solution was refluxed an additional thirty minutes and then concentrated under reduced pressure. lhe residue was made strongly alkaline with potassium hydroxide so that all of the stannic hydroxide remained in solution and the solution extracted with ether. The ether extracts were washed until neutral and then dried over anhydrous magnesium sulfate. After removal of the drying agent and concentration of the solution, a yellow solid was obtained which, after crystallization from benzenepetroleum ether (90-100"), yielded 11 g. or 82% of spiro [cyclohexane-l,1'-x-aminoindanone3'l melting at l16-118. Further recrystallization from methanol-water mixtures and finally sublimation at 120 and 0.5 mm. produced a nearly white crystalline compound melting at 125-126".

The amino-ketone g.) with 10 g. of hydroxylamine hydrochloride in 55 ml. of absolute alcohol and 23 ml. of pyridine was refluxed for three hours. The solution was concentrated to dryness under reduced pressure and the residue dissolved in alcohol, clarified, filtered, and the oxime precipitated by the slow addition of water. The oxime of spiro [cyclohexane-1,1'-x-aminoindanone-] (10 g.) so obtained was recrystallized from methanol-water mixtures and melted at 178-180.

Spiro [cycloherane 1,1'-x-hydro:cyindunone- 3'].A slurry of 10.5 g. of the aminoketone in 11 ml. of concentrated sulfuric acid and ml. of water was stirred and cooled to 0 and 3.5 g. of sodium nitrite in 20 ml. of water was added dropwise over a period of forty-five minutes. When a persistent test for nitrous acid was obtained, urea was added to destroy the excess nitrous acid. The solution was filtered and 5 ml. of concen trated sulfuric acid in 20 ml. of water was added to the filtrate and the solution heated on a steam bath for one and a quarter hours. The oily top layer which was formed from this reaction solidified on cooling. The crude brown hydroxyketone was dissolved in ether, the ether layer extracted with aqueous potassium hydroxide, clarified with charcoal, filtered and neutralized in the cold with hydrochloric acid to produce 7.6 g. or 72% of yellow crystalline spiro [cyclohexane-1,1- x-hydroxyindanone-3]. Further recrystallization from alcohol-water mixtures and finally sublimation at 160 and 0.03 mm. yielded a slightly yellow compound melting at 159-460".

Spiro [cycloherane 1,1 a: ethoryindcnone- 3'].The hydroxyketone was ethylated with diethyl sulfate according to the directions for the preparation of vertraldehyde. The product was isolated by ether extraction of the alkaline medium. After drying and removal of the solvent, the residue was distilled at /0.7 mm. Spiro lcyclohexane-1,1-x-ethoxyindanone-3l so obtained, solidified and after recrystallization from petroleum ether (SO-60) and sublimation at 80 and 0:1 mm. melted at Gil-70.

The yield of this reaction was low, however, the starting hydroxy ketone could be recovered by acidification of the original reaction medium after the extraction with ether.

The oxime of spiro [cyclohexane-1,1'x-ethoxyindanone-3l prepared in the usual manner, recrystallized from alcohol-water mixtures, and finally sublimed at reduced pressure melted at 151.5-152".

Spiro [cycloherane 1,1 3-amino-ac-ethoscyindane].The oxime of spiro lcyclohexane- 1,1-x-ethoxyindanone-3l (2.7 g.) in 50 ml. of glacial acetic acid was hydrogenated at room temperature and 25 pounds of hydrogen using 1.1 g. of Adams catalyst. After cessation of the absorption of hydrogen, the catalyst was filtered and the filtrate was cooled and made alkaline. The alkaline solution was extracted with ether, dried with anhydrous magnesium sulfate, and concentrated to dryness after removal of the drying agent. The remaining brown oil was converted into the amine hydrochloride by passing hydrogen chloride gas through a dry ether solution of the amine. Recrystallization from methanolether mixtures produced 2.8 g. of spiro-[cyclohexane 1,1-3'-amino-x-ethoxyindane] hydrochloride melting at 234-237.

Example XVIII A compound having the formula:

may be prepared as follows:

Spiro [cyclohescane 1,1-3'-dimethyZamino-.rethylaminoindane] .--A solution of 1.5 g. of the N- decrease:

acetylz derivative of the spiro- Ecyclohexa-ne- 1-,1'-xamino 3' dimethyla-minoindanel- (prepared by the reaction of this diamine with acetic anhydride in the presence of pyridine in the manner which is well known to those skilled in the art, and having a melting point of 183-184 C. after three recrystallizations from acetone):

Example XIX A compound having the formula:

may be prepared as follows:

Spiro [cyclohexane 1,1-x-cyano-3'-dimethylaminoindanel (2.5 g.) in 50 ml. of anhydrous ether was added dropwise to 20 ml. of 1.3 molar lithium aluminum hydride in anhydrous ether. After the addition, the mixture was stirred for another hour at room temperature. The mixture was then cooled in an ice bath and decomposed with water. The ether layer was separated and concentrated to dryness. The resulting brown oil was treated with benzoyl chloride and sodium hydroxide to form the solid N-benzoyl derivative. The solid was filtered, washed thoroughly with cold alcohol and then hydrolyzed by boiling with 50 ml. of concentrated hydrochloric acid and 50 m1. of water for ninety-six hours. The cooled acid solution was extracted with ether and the ether layer rejected. The aqueous acid layer was carefully neutralized and the neutral solution extracted with ether. The dried ether solution was concentrated to give 1.2 g. of spiro [cyclohexane 1,1 -x-aminomethyl-3 -dimethylaminoindanel.

In the foregoing examples it will be understood that in lieu of the methyl group other lower alkyl groups such as ethyl, propyl, etc., may be incorporated in the molecule by proper selection of the reacting materials in the manner obvious to those skilled in the art. Likewise, it will be understood that the alkoxy group may be methoxy, ethoxy, propoxy, etc., the acyl group may be acetyl, propionyl, butyryl, etc., and the halogen may be the chloride, bromide, iodide, fluoride, etc.

The term D. isusedhereinaaanabbreviation for the minimal efiective dosage for 50% of the animals tested. The term L.D5o is used herein as an abbreviationfor the lethal dosage for 50% of the animals tested.

It will be understood that other modifications may be made in the foregoing. examples without departing from the scope'of the invention. It is intended, therefore, that the patent shall cover by suitable expression in the appended claims the features of patentable novelty residing in the in vention. V

This appl'icationis a continuation-in-part of application Serial No. 150,809, filed March 20, 1950 now abandoned.

We claim:

1. A compound represented by the formula in which R1 and R2 are selected from the group consisting of I-I- and lower alkyl-, and X represents a member of the group consisting of halogen-, HO-, NO2- and CN-.

2. A compound represented by the formula 3. A compound represented by the formula 4. A compound represented by the formula 5. A compound represented by the formula H N-C 6. A compound represented bythe formula 7 References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 5 2,585,969 Schwartzman et, a1. Feb. 19, 1952 2,586,487 Schwartzman et a1. Feb. 19, 1952 OTHER REFERENCES Schwartzman: Jour. Org. Chem, 15, 517-524 (1950).

GILBERT FORREST WOODS; JR." LOUIS H. SCHWARTZMAN. 

1. A COMPOUND REPRESENTED BY THE FORMULA 